tbuckley/cabot-search huggingface dataset:
Safety and efficacy of etigilimab in combination with nivolumab in select recurrent/advanced solid tumors.
Authors: Meredith McKean, Ecaterina Elena Dumbrava, Omid Hamid, Priscilla Merriam, Niharika B. Mettu, Justin A Call, Ann M. Kapoun, Jennifer Lucas, Mahesh Seetharam, Ulka N. Vaishampayan, Saravut John Weroha, Suba Krishnan, Angela Joy George
Journal: Journal of Clinical Oncology (2022)

2651 Background: Etigilimab (etig), a humanized IgG1 monoclonal antibody, blocks TIGIT interaction with PVR (poliovirus receptor) and inhibits downstream signalling with target cell killing. Etig +/- nivolumab (nivo) showed acceptable safety and preliminary activity in a FIH Phase 1a/b study in solid tumors. ACTIVATE, an open-label Phase 1b/2 basket study is evaluating further efficacy, safety, tolerability and PK/PD of etig+nivo. This is a preliminary efficacy and safety analysis from ACTIVATE. Methods: Subjects with advanced/metastatic solid tumors without curative/standard of care therapies are given IV etig+nivo Q2W until disease progression or intolerable toxicity. Six open cohorts are enrolling in parallel: endometrial cancer (post-front-line platinum), endometrial cancer (2-3 prior lines), PD-L1+ checkpoint-inhibitor-naïve (CPI-n) cervical cancer, rare cancers (germ cell tumor (GCT), sarcoma, uveal melanoma), ovarian cancer (post-front-line platinum) and TMB-h/MSS, (TMB &gt;10mut/mb) tumors. Tumor assessments are done every 8 weeks following baseline scan. Primary endpoint is investigator-assessed ORR by RECIST 1.1. Secondary endpoints include duration of response and safety. Results: Of 27 efficacy-evaluable subjects enrolled in the 6 open cohorts with minimum 1 staging scan or radiological/clinical progression at data cut-off of 02/10/22, 12 had clinical benefit with 1 complete response (CR), 2 partial responses (PRs) and 9 stable diseases (SDs) and 15 had radiological/clinical progressive disease (PD), with an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Conclusions: Etig+nivo is safe and well tolerated with no new safety signals. Early efficacy was noted in cervical cancer (1CR, 1PR and 1SD) and uveal melanoma (3 SDs &gt;20 weeks). Encouraging activity was also noted in ovarian cancer and post-CPI treated TMB-H/MSS NSCLC. These early data support continued evaluation of the combination of etig+nivo. Clinical activity was notable as below. Clinical trial information: NCT04761198. [Table: see text]
Erdafitinib in pediatric patients with advanced solid tumors with fibroblast growth factor receptor (<i>FGFR</i>) gene alterations: RAGNAR study pediatric cohort.
Authors: Olaf Witt, Birgit Geoerger, Uta Dirksen, Sameer Farouk Sait, David A. Reardon, Kent C. Shih, Blanca D. Diez, Eliana Maria Monteiro Caran, Shuhei Karakawa, Kim Stuyckens, Huimin Liao, Saltanat Najmi, Constance Hammond, Ademi E. Santiago-Walker, Hussein Sweiti
Journal: Journal of Clinical Oncology (2022)

TPS10058 Background: FGFR gene alterations have been observed in pediatric patients with cancers and represent potentially targetable genomic variants. Gliomas (high- and low-grade) and soft tissue sarcomas are among the pediatric solid tumors that may harbor FGFR alterations. Erdafitinib is a selective pan-FGFR inhibitor approved in patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR2/3 alterations. RAGNAR (NCT04083976) is an ongoing single-arm, open-label, phase 2 histology-agnostic study investigating the efficacy and safety of erdafitinib in patients with advanced solid tumors exhibiting FGFR alterations after failure of standard systemic therapies. Here we describe the pediatric study cohort. Methods: The pediatric cohort (n = 26, planned) includes patients (≥ 6- &lt; 18 y) with advanced solid tumors (measurable disease per RECIST v.1.1 or RANO [brain tumors]) with FGFR mutations, gene fusions, or internal tandem duplication (patients with FGFR amplification are not eligible) identified via local test reports or central molecular testing. Eligible patients will have received ≥ 1 lines of prior systemic therapy, have exhausted or be unable to tolerate standard-of-care therapies, and have documented disease progression and measurable disease. In addition, up to 6 patients in this cohort will be allowed to be treatment naive. Children and adolescents will be treated with oral erdafitinib, allowing pharmacodynamically guided uptitration based on serum phosphate levels to maximize efficacy. Treatment will continue until progressive disease. The primary end point is overall response rate (ORR) assessed by an independent review committee. Secondary efficacy end points include ORR assessed by the investigator, duration of response, disease control rate, clinical benefit rate, progression-free survival, and overall survival. Other secondary end points are pharmacokinetic exposure parameters, incidence/severity of adverse events, and change from baseline in patient-reported health status. End-of-treatment visit will occur 30 days after the last dose of erdafitinib. A follow-up phase will continue until death, withdrawal of consent, loss to follow-up, or end of study. As of January 2022, 3 patients have been enrolled. Clinical trial information: NCT04083976.
Clinical validation of a deep-learning–based model to predict lung cancer risk from chest X-rays.
Authors: Anika Walia, Vineet Raghu, Aniket Zinzuwadia, Inga Tolin Lennes, Michael T Lu
Journal: Journal of Clinical Oncology (2022)

10507 Background: Screening with chest CT prevents lung cancer death, but only 5% of eligible Americans are screened. The updated 2022 Centers for Medicare and Medicaid Services (CMS) criteria expand eligibility to 50-77 year-olds, current or former (&lt;15 years) smokers, with a ≥20 pack-year history. However, smoking quit date and pack-years are often not available in the electronic medical record (EMR), stymying identification of high-risk smokers for lung cancer screening (LCS). We previously developed a free, open-source deep-learning model (CXR-LC) that identifies smokers at high risk of lung cancer better than the 2015 CMS criteria, based on a chest X-ray (CXR) image automatically extracted from the EMR. CXR-LC was developed in the PLCO trial, an asymptomatic LCS population. The present study externally validates CXR-LC using existing CXRs obtained through usual care and compares CXR-LC to the expanded 2022 CMS lung screening eligibility criteria. Methods: Current or former smokers who had a routine clinical CXR in 2013-2014 were included. Patients with known lung cancer or who were undergoing LCS were excluded. Smoking status and 2022 CMS LCS eligibility were determined by manual review of the EMR. The primary outcome was 6-year incident lung cancer, identified using International Classification of Disease (ICD) codes and confirmed through discharge summaries and pathology reports. The CXR-LC model and the 2022 CMS eligibility criteria were compared for prediction of 6-year incident lung cancer. Results: Among 10,784 patients (mean age 63.1± 6.8 years; 61.0% male), CMS eligibility could be determined in 45% (4,886/10,784), with 55% missing pack-year or quit date data. In this population, 3.9% (191/4,886) developed lung cancer. The 2022 CMS criteria missed 57% (109/191) of lung cancers, while CXR-LC missed 8.9% (17/191, p &lt; 0.001). After adjusting for sex, race, and prevalent COPD, the hazard ratio for CXR-LC eligibility (3.6, 95% CI [2.2,6.0]) was greater than for CMS eligibility (2.7, 95% CI [2.0,3.7]). In the 5,897 patients for whom CMS eligibility could not be determined, CXR-LC eligible patients had a 3-fold higher rate of lung cancer than CXR-LC ineligible patients (3.8% vs. 1.3%, p &lt; 0.001). All CXR-LC eligible groups had 6-year lung cancer incidence &gt;3.5%, above accepted screening risk thresholds of &gt;1.5% and &gt;2%. Conclusions: Using routine CXRs from the EMR, CXR-LC identified high-risk smokers who may benefit from LCS with CT, complementary to the 2022 CMS eligibility criteria. [Table: see text]
Long-term efficacy and safety of anlotinib in advanced sarcomas.
Authors: Weitao Yao, Xinhui Du, Jiaqiang Wang, Peng Zhang, Xiaohui Niu, Xin Wang
Journal: Journal of Clinical Oncology (2022)

e23564 Background: Treatment of sarcomas has advanced in recent years partly because of the application of multitarget tyrosine kinase inhibitor (TKI) drugs. Anlotinib is an oral TKI with the dual effects of antiproliferation and antiangiogenesis, and it has a therapeutic effect with good tolerance and low side effects. In theory, physicians can gain long-term tumor control with anlotinib in certain advanced sarcomas. Methods: We conducted a retrospective analysis of patients with advanced sarcomas with measurable target lesions who had been treated in our ward since 2018. There were 22 patients who had taken anlotinib regularly for more than 12 months. Their general information, clinical efficacy, and toxicities were statistically analyzed. We used a swimmer plot to observe the efficacy and duration of the drugs and a waterfall plot to express the best treatment effect. Results: There were 14 male and 8 female patients, ranging in age from 14 to 75 (44.77 on average) years. The primary sarcomas were ASPS in five cases; synovial sarcoma (SS) in four cases; LMS in three cases; epithelioid sarcoma (ES) and UPS in two cases each; and clear cell sarcoma, RMS, angiosarcoma (AS), fibrosarcoma (FS), pleomorphic liposarcoma (LS), and osteosarcoma (OS) in one case each. The sites of metastasis were the lung in 15 cases, lymph nodes in 4 cases, and multiple sites in 3 cases. Therapies were as follows: first-line therapy (6 cases), second-line therapy (9 cases), third-line therapy (5 cases), and more than third-line therapy (2 cases). The current therapy protocols were nine cases with oral anlotinib alone, nine cases with combination chemotherapy, and four cases with combination immunotherapy (anti-PD1). The best clinical efficacy of this group was complete response (CR) in four cases (18.18%), partial response (PR) in five cases (22.73%), and stable disease in 13 cases (59.09%), with an overall response rate of 40.91% and the longest lasting time of 26, 16, 38 months in different response groups. The mean of progression-free survival (PFS) was 23.32 months. The main adverse effects included myelosuppression in seven cases (31.82%), hypertension in three cases (13.64%), and hand-foot syndrome and weakness in two cases (9.10%). Severe adverse effects included hypothyroidism with weakness in one case and wound ulceration with pneumothorax formation in another case. Conclusions: Anlotinib monotherapy or combination therapy can be an effective and safe choice for some advanced sarcomas with a longer maintenance time and acceptable side effects. Besides, anlotinib combined with anti-PD1 therapy has better therapeutic efficacy for specific diseases such as ASPS and ES. Anlotinib combined with chemotherapy has therapeutic efficacy for SS, LMS, FS, and RMS. Clinical efficacy such as CR and PR may be a prediction of long-term PFS in some advanced sarcomas.
Time for paying attention to fluoropyrimidine-associated cardiotoxicity: A pooled data analysis for epidemiology based on 60537 cases.
Authors: Yajie Lu, Zuoyao Long, Wei Pan, Shi-Zhou Deng, Qiong-Yi Dou, Xiang-Xu Wang, Zhen Wang, Hong-Mei Zhang
Journal: Journal of Clinical Oncology (2022)

12071 Background: With the rise of cardio-oncology discipline, treatment-related cardiotoxicity has become a growing concern. However, fluoropyrimidine induced cardiotoxicity has been underestimated for a long time. The aim of this study was to comprehensively investigate the incidence and profiles of the cardiotoxicity associated with fluoropyrimidine using a pooled data meta-analysis. Methods: A systematic literature review was performed using PubMed, Embase, Medline, Web of Science, Cochrane library databases and clinical trials on studies published between the establishment of each database and March 31, 2021, investigating fluoropyrimidine associated cardiotoxicity (FAC). The main outcome was pooled incidence of FAC, and the secondary outcome were specific treatment-related cardiac AEs. Random-effects or fixed-effects modeling was used for analyses according to the heterogeneity assessed by Cochran’s Q test. Subgroup analysis and meta-regression were conducted to explore the source of heterogeneity, and the incidence of FAC was compared among different clinical characteristics. The protocol was registered in PROSPERO (No. CRD42021282155). Results: Two hundred and six studies involving 60537 patients were included in this meta-analysis, covering 31 countries or regions in the world. The pooled incidence of FAC was 5.18% (95% CI 4.32%-6.10%) for all grade and 1.5% (95% CI 1.09%-1.96%) for grade 3 or higher. A total of 0.29% of patients died from severe cardiotoxicity. Cardiac ischemia and arrhythmia were the two most common cardiac AEs, occurring in 2.31% (95% CI 1.70%-3.00%) and 1.69% (95% CI 1.08%-2.42%) of patients, respectively. ECG alterations occurred in 5.85% (95% CI 3.4%-8.9%) of patients, indicating asymptomatic ECG alterations in a subset of the population. The incidence of cardiotoxicity varied among different regions, gender, cancer types and treatment regimens. Studies conducted in Asia outlined a significant higher pooled incidence of FAC than in Europe (χ2 = 4.47, p = 0.03) and America (χ2 = 4.49, p = 0.03). Female population had a lower pooled incidence than general population (χ2 = 9.90, p= 0.01). The highest pooled incidence was observed in esophagus cancer (10.53%, 95% CI 5.8%-16.35%), and the lowest occurred in breast cancer (3.66%, 95% CI 2.4%-5.12%). In addition, combination therapy, high cumulative dose, anthracycline addition, and pre-existing cardiac disorder significantly increased the risk of FAC ( p&lt; 0.05). No obvious publication bias was detected by funnel plots and Egger’s test (p &lt; 0.05), and the stability of our results was confirmed by the sensitivity analysis. Conclusions: FAC is not a rare condition during treatment containing fluoropyrimidines. Our results provide comprehensive global data on epidemiology of FAC, potentially representing an important reference on cancer management in clinical practice.
Associations between genomic instability score (GIS), molecular characterization, and clinical outcomes in high grade serous ovarian cancers (HGSOC).
Authors: Catherine Watson, Jessie Paradis, Samantha M. Thomas, Kirsten Timms, Michael Perry, TC Perry, Angeles Alvarez Secord
Journal: Journal of Clinical Oncology (2022)

e17596 Background: To describe the molecular profiles of tumors with a positive GIS status (GI+) in patients with newly diagnosed BRCA wild-type HGSOC and to examine possible associations between genomic mutations and survival outcomes in these patients. Methods: Genetic testing results of patients who underwent both somatic BRCA1/BRCA2 and germline multigene panel testing between 1/1/2015 and 12/1/2020 were prospectively collected. Patients had multigene panel germline testing in tandem with Myriad somatic BRCA1/2 testing and GIS assay. Expanded somatic NGS testing (108 gene panel) was then performed on GIS+ (GIS ≥42) tumor samples from women without somatic or germline BRCA mutations. The primary outcomes were the type and frequency of genomic mutations, which were grouped according to the following pathways: DNA-repair related (separated into homologous recombination (HR), Fanconi anemia (FA), other DNA repair related pathway) or non-DNA repair related. GIS and molecular profiles of tumors from patients who recurred versus those who did not recur were compared. Results: 143 women with HGSOC underwent both germline and somatic testing. 18/143 (12.5%) tumors with negative germline multigene panel and negative somatic BRCA1/2 testing were GIS+. 17/18 (94.4%) GIS+ tumors had pathogenic TP53 mutations. While all samples had at least one DNA repair related variant, only 22.2% had an HR-associated variant, and 16.7% had an FA variant. At time of analysis, 10 patients had recurred and 8 patients had not recurred. Median PFS of those who recurred was 15.8 months (range 4.8-30.1 months). Patients who recurred had lower GIS (median 47.5 vs. 69.5, p = 0.04), but they had no appreciable differences in gene or pathway alterations when compared to those who did not recur. Conclusions: Known pathogenic alterations in DNA repair pathways commonly associated with HR were rare in this cohort of BRCA negative HGSOC patients with GIS+ tumors. However, there was a high frequency of other DNA repair pathway alterations. Further investigation of the molecular signatures associated with recurrence are needed to identify potential novel targets. Lower GIS in this cohort were associated with higher risk of recurrence, although this finding must be validated in the setting of larger studies. [Table: see text]
Isoflavonoid-based therapeutics to remodel immunologically cold tumors in nasopharyngeal carcinoma.
Authors: Ngar Woon Kam, Olivier Laczka, Desmond Hung, Xiang Li, Wei Dai, George Tsao, Victor Ho-Fun Lee, Dora Lai Wan Kwong
Journal: Journal of Clinical Oncology (2022)

e14534 Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern China and is well-known to be heavily infiltrated by lymphocytes and constitute a unique but poorly defined tumor microenvironment. We aimed at delineating and defining the contribution of idronoxil (IDX), a synthetic flavonoid derivative, in restoring sensitivity to apoptosis and potentially modulating the immune microenvironment of NPC. Methods: Using multiplexed staining, we measured the levels of ENOX2 (IDX’s target), CD8 (cytotoxic T cell) and pan-cytokeratin (tumor marker) in 86 NPC patients’ cancerous specimens in tissue microarray format. NPC tissue bulk RNA-Seq and affymetrix microarray public datasets were gathered to examine ENOX2 significance. Interaction between ENOX2-expressing tumor cell lines (C17 and NPC43) and T cells were also studied. In vivo, antitumor effects of IDX on the growth of NPC43+ve tumors in nude mice and humanized mice were studied. Results: We performed median density as cut-off and tumors can be classified as hot or cold. 68.6% “cold”-phenotype tumors were observed in our cohort and the top 20% patients with highly positive ENOX2-expresing tumor cells showed lower number of CD8 infiltrates. Publicly dataset showed that highly expressed ENOX2 group associated with poorer prognosis (log-rank test p = 0.041). In vitro, we observed increased migration of T cells towards cancer cells when tumor cells were pre-treated with the combination of IDX and cisplatin (IDX+Cis) compared with monotherapy (IDX or cis alone) or untreated. We also observed increased susceptibility of tumor cells to T cell cytotoxicity when both IDX and Cis were added. In nude mice, IDX+Cis significantly decreased the tumor growth compared to saline-treated group. In humanized mice, upon treatment, we found 1.69-fold (p = 0.039) more CD3+ T cells in the tumor than in the blood when compared to control group. In humanized mice, the ratio between human T cell levels in tumor and blood was increased by the IDX+Cis compared to control group (1.67-fold, p = 0.01 by t-test). Conclusions: Distinct immunospatial profiles could be associated with clinicopathologic characteristics. The ability of IDX to modulate T cell populations indicates the potential of IDX to enhance the efficacy of current chemotherapy treatments in NPC by upregulating cellular trafficking toward tumor.[Table: see text]
Cancer PD1/PD-L1 inhibitor efficacy as stratified by smoking status: A population large database study.
Authors: Zachary D. Urdang, SoHye Park, Ramez Philips, Hee-Soon Juon, Jennifer Maria Johnson, Ubaldo E. Martinez-Outschoorn, Joseph M. Curry
Journal: Journal of Clinical Oncology (2022)

2594 Background: Delineating clinical factors that predict immune checkpoint inhibitor (ICI) cancer therapy response is a pressing need and smoking is a known factor. In this study we leveraged a large international (heavily US) database to perform the largest study to date for all cancers and major cancer sub-sites/types. Methods: Utilizing the TriNetX electronic health records database with 84.3M patients we tested the hypotheses that ICI response stratifies based on smoking, and continued smoking after ICI. Queries were constructed using billing codes for all cancer types treated with an ICI with and without smoking. The smoking cohort was subsequently sub-stratified for continuing vs cessation of smoking after ICI. Next, using ICI therapy as the index event, odds ratios (OR) with 95% confidence intervals for death, and treatment related secondary outcomes were calculated between 0.5-5 years after ICI treatment. Statistics were calculated using TriNetX's integrated statistical platform before and after 1:1 propensity score matching (PSM) for smoking related co-morbidities. Results: The OR for death after ICI therapy for smokers ( n 13336) vs non-smokers ( n 38973) for any cancer type was 1.27(1.21-1.34) and decreased to 1.11(1.04-1.19) after PSM. Further sub-stratifying the smoking cohort for continued vs cessation of smoking yielded ORs of 1.13(1.03-1.24) and 1.12(1.01-1.24) before and after PSM respectively. Secondary outcomes included ablative surgery, chemotherapy, radiation, and secondary neoplasm. ORs for receiving chemotherapy, and developing secondary neoplasm were most consistently statistically significant across comparisons. Conclusions: Smoking adversely potentiates cancer outcomes after ICI therapy. PSM for smoking related comorbid conditions decreased the magnitude of this association although the findings remained clinically and statistically significant. This highlights the key role in smoking related co-morbid conditions as prognostic clinical characteristics. Furthermore, this suggests that smoking affects ICI on a mechanistic/biological level beyond increasing burden of medical comorbidities. Lastly, as smoking cessation also improved outcomes after PSM this further suggests that washout of smoke toxins has a mechanistic/biological effect on ICI activity. [Table: see text]
Capecitabine for advanced biliary tract cancers during COVID-19 pandemic.
Authors: Chandan Krushna Das, T D Yadav, Harjeet Singh
Journal: Journal of Clinical Oncology (2022)

e16116 Background: Despite chemotherapy, metastatic gall bladder cancers (mGBC) have the worst prognosis. Many patients are unfit for the standard of care Cisplatin-based injectable chemotherapy. The study evaluates single-agent Capecitabine as an effective therapy option for frontline advanced GBC patients in a COVID pandemic affected hospital access. Methods: This is a retrospective analysis of mGBC patients treated at the PGIMER Medical Oncology Clinic between December 2019 and August 2021. Patients with an Eastern Cooperative Oncology Group performance rating of 0-2 were given Capecitabine 1,000 mg/m2 twice daily for 14 days. The primary goal was to measure progression-free survival (PFS). The secondary objectives were overall survival (OS), safety, and the need for biliary diversion. Results: A total of 72 patients were analyzed. With a median follow up of 12 months, the median PFS was 5.4 months (4.0-9.1), and the interim overall survival OS was 11.9 months (5.2-16). During treatment, 12% of patients required biliary diversion. The safety profile was consistent with previous capecitabine use, and no new safety signals were detected. There were 9.7 percent (7/72) of grade 3/4 adverse events (AEs) reported. Due to poor tolerability, one-third of patients (30.5%) required dose reduction/interruption. Conclusions: In a COVID pandemic situation, Capecitabine is safe, effective, and comparable efficacy for patients with advanced mGBC. However, It needs to be evaluated in randomized clinical trials comparing the standard of care.[Table: see text]